Aerosol forming device for use in inhalation therapy

ABSTRACT

Inhalation delivery of aerosols containing small particles from a device that forms drug containing aerosols for use in inhalation therapy. A device for delivering drug containing aerosols for inhalation therapy is provided. The device includes a housing and an airway that has a gas/vapor mixing airway. The airway further includes a subassembly, which has a metallic substrate coated on its surface with a composition comprising a drug.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/078,600, entitled “Aerosol Forming Device For Use In InhalationTherapy”, filed Apr. 1, 2011 which is a continuation of U.S. applicationSer. No. 10/146,080, filed May 13, 2002, now U.S. Pat. No. 7,942,147,which is a continuation-in-part of U.S. patent application Ser. No.10/057,198 entitled “Method and Device for Delivering a PhysiologicallyActive Compound,” filed Oct. 26, 2001, Lloyd et al., now abandoned andof U.S. patent application Ser. No. 10/057,197 entitled “AerosolGenerating Device and Method,” filed Oct. 26, 2001, Wensley et al., nowU.S. Pat. No. 7,766,013, each of said application Ser. Nos. 10/146,080,10/057,198, 10/057,197 further claims priority to U.S. ProvisionalApplication Ser. No. 60/296,225 entitled “Aerosol Generating Device andMethod,” filed Jun. 5, 2001, Wensley et al, the entire disclosures ofeach of the referenced application is hereby incorporated by reference.Any disclaimer that may have occurred during the prosecution of theabove-referenced applications is hereby expressly rescinded, andreconsideration of all relevant art is respectfully requested.

FIELD OF THE INVENTION

The present invention relates to the inhalation delivery of aerosolscontaining small particles. Specifically, it relates to a device thatforms drug containing aerosols for use in inhalation therapy.

BACKGROUND OF THE INVENTION

Currently, there are a number of approved devices for the inhalationdelivery of drugs, including dry powder inhalers, nebulizers, andpressurized metered dose inhalers. Along with particular drugs, however,the devices also deliver a wide range of excipients.

It is desirable to provide a device that can produce aerosols in theabsence of excipients. The provision of such a device is an object ofthe present invention.

SUMMARY OF THE INVENTION

The present invention relates to the inhalation delivery of aerosolscontaining small particles. Specifically, it relates to a device thatforms drug containing aerosols for use in inhalation therapy.

In a device aspect of the present invention, a device for deliveringdrug containing aerosols for inhalation therapy is provided. The deviceincludes a housing and an airway that has a gas/vapor mixing airwayarea. The airway further includes a subassembly, which has a metallicsubstrate coated on its surface with a composition comprising a drug.

Typically, the device further includes a heater system. Preferably, theheater system is an inductive heater system. More preferably, it is aninductive heating system having a ferrite toroid.

Typically, the airway contains a restricted cross-sectional area alongthe gas/vapor mixing area. Preferably, the airway further includes meansfor causing turbulence as air moves through the airway.

Typically, the drug has a decomposition index less than 0.15.Preferably, the drug has a decomposition index less than 0.10. Morepreferably, the drug has a decomposition index less than 0.05.

Typically, the drug of the composition is of one of the followingclasses: antibiotics, anticonvulsants, antidepressants, antiemetics,antihistamines, antiparkisonian drugs, antipsychotics, anxiolytics,drugs for erectile dysfunction, drugs for migraine headaches, drugs forthe treatment of alcoholism, drugs for the treatment of addiction,muscle relaxants, nonsteroidal anti-inflammatories, opioids, otheranalgesics and stimulants.

Typically, where the drug is an antibiotic, it is selected from one ofthe following compounds: cefmetazole; cefazolin; cephalexin; cefoxitin;cephacetrile; cephaloglycin; cephaloridine; cephalosporins, such ascephalosporin C; cephalotin; cephamycins, such as cephamycin A,cephamycin B, and cephamycin C; cepharin; cephradine; ampicillin;amoxicillin; hetacillin; carfecillin; carindacillin; carbenicillin;amylpenicillin; azidocillin; benzylpenicillin; clometocillin;cloxacillin; cyclacillin; methicillin; nafcillin; 2-pentenylpenicillin;penicillins, such as penicillin N, penicillin O, penicillin S,penicillin V; chlorobutin penicillin; dicloxacillin; diphenicillin;heptylpenicillin; and metampicillin.

Typically, where the drug is an anticonvulsant, it is selected from oneof the following compounds: gabapentin, tiagabine, and vigabatrin.

Typically, where the drug is an antidepressant, it is selected from oneof the following compounds: amitriptyline, amoxapine, benmoxine,butriptyline, clomipramine, desipramine, dosulepin, doxepin, imipramine,kitanserin, lofepramine, medifoxamine, mianserin, maprotoline,mirtazapine, nortriptyline, protriptyline, trimipramine, viloxazine,citalopram, cotinine, duloxetine, fluoxetine, fluvoxamine, milnacipran,nisoxetine, paroxetine, reboxetine, sertraline, tianeptine,acetaphenazine, binedaline, brofaromine, cericlamine, clovoxamine,iproniazid, isocarboxazid, moclobemide, phenyhydrazine, phenelzine,selegiline, sibutramine, tranylcypromine, ademetionine, adrafinil,amesergide, amisulpride, amperozide, benactyzine, bupropion, caroxazone,gepirone, idazoxan, metralindole, milnacipran, minaprine, nefazodone,nomifensine, ritanserin, roxindole, S-adenosylmethionine, tofenacin,trazodone, tryptophan, venlafaxine, and zalospirone.

Typically, where the drug is an antiemetic, it is selected from one ofthe following compounds: alizapride, azasetron, benzquinamide,bromopride, buclizine, chlorpromazine, cinnarizine, clebopride,cyclizine, diphenhydramine, diphenidol, dolasetron methanesulfonate,droperidol, granisetron, hyoscine, lorazepam, metoclopramide,metopimazine, ondansetron, perphenazine, promethazine, prochlorperazine,scopolamine, triethylperazine, trifluoperazine, triflupromazine,trimethobenzamide, tropisetron, domeridone, and palonosetron.

Typically, where the drug is an antihistamine, it is selected from oneof the following compounds: azatadine, brompheniramine,chlorpheniramine, clemastine, cyproheptadine, dexmedetomidine,diphenhydramine, doxylamine, hydroxyzine, cetrizine, fexofenadine,loratidine, and promethazine.

Typically, where the drug is an antiparkisonian drug, it is selected oneof the following compounds: amantadine, baclofen, biperiden,benztropine, orphenadrine, procyclidine, trihexyphenidyl, levodopa,carbidopa, selegiline, deprenyl, andropinirole, apomorphine,benserazide, bromocriptine, budipine, cabergoline, dihydroergokryptine,eliprodil, eptastigmine, ergoline pramipexole, galanthamine, lazabemide,lisuride, mazindol, memantine, mofegiline, pergolike, pramipexole,propentofylline, rasagiline, remacemide, spheramine, terguride,entacapone, and tolcapone.

Typically, where the drug is an antipsychotic, it is selected from oneof the following compounds: acetophenazine, alizapride, amperozide,benperidol, benzquinamide, bromperidol, buramate, butaperazine,carphenazine, carpipramine, chlorpromazine, chlorprothixene,clocapramine, clomacran, clopenthixol, clospirazine, clothiapine,cyamemazine, droperidol, flupenthixol, fluphenazine, fluspirilene,haloperidol, mesoridazine, metofenazate, molindrone, penfluridol,pericyazine, perphenazine, pimozide, pipamerone, piperacetazine,pipotiazine, prochlorperazine, promazine, remoxipride, sertindole,spiperone, sulpiride, thioridazine, thiothixene, trifluperidol,triflupromazine, trifluoperazine, ziprasidone, zotepine, zuclopenthixol,amisulpride, butaclamol, clozapine, melperone, olanzapine, quetiapine,and risperidone.

Typically, where the drug is an anxiolytic, it is selected from one ofthe following compounds: mecloqualone, medetomidine, metomidate,adinazolam, chlordiazepoxide, clobenzepam, flurazepam, lorazepam,loprazolam, midazolam, alpidem, alseroxlon, amphenidone, azacyclonol,bromisovalum, buspirone, calcium N-carboamoylaspartate, captodiamine,capuride, carbcloral, carbromal, chloral betaine, enciprazine,flesinoxan, ipsapiraone, lesopitron, loxapine, methaqualone, methprylon,propanolol, tandospirone, trazadone, zopiclone, and zolpidem.

Typically, where the drug is a drug for erectile dysfunction, it isselected from one of the following compounds: cialis (IC351),sildenafil, vardenafil, apomorphine, apomorphine diacetate,phentolamine, and yohimbine.

Typically, where the drug is a drug for migraine headache, it isselected from one of the following compounds: almotriptan, alperopride,codeine, dihydroergotamine, ergotamine, eletriptan, frovatriptan,isometheptene, lidocaine, lisuride, metoclopramide, naratriptan,oxycodone, propoxyphene, rizatriptan, sumatriptan, tolfenamic acid,zolmitriptan, amitriptyline, atenolol, clonidine, cyproheptadine,diltiazem, doxepin, fluoxetine, lisinopril, methysergide, metoprolol,nadolol, nortriptyline, paroxetine, pizotifen, pizotyline, propanolol,protriptyline, sertraline, timolol, and verapamil.

Typically, where the drug is a drug for the treatment of alcoholism, itis selected from one of the following compounds: naloxone, naltrexone,and disulfiram.

Typically, where the drug is a drug for the treatment of addiction it isbuprenorphine.

Typically, where the drug is a muscle relaxant, it is selected from oneof the following compounds: baclofen, cyclobenzaprine, orphenadrine,quinine, and tizanidine.

Typically, where the drug is a nonsteroidal anti-inflammatory, it isselected from one of the following compounds: aceclofenac, alminoprofen,amfenac, aminopropylon, amixetrine, benoxaprofen, bromfenac, bufexamac,carprofen, choline, salicylate, cinchophen, cinmetacin, clopriac,clometacin, diclofenac, etodolac, indoprofen, mazipredone,meclofenamate, piroxicam, pirprofen, and tolfenamate.

Typically, where the drug is an opioid, it is selected from one of thefollowing compounds: alfentanil, allylprodine, alphaprodine,anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol,carbiphene, cipramadol, clonitazene, codeine, dextromoramide,dextropropoxyphene, diamorphine, dihydrocodeine, diphenoxylate,dipipanone, fentanyl, hydromorphone, L-alpha acetyl methadol,lofentanil, levorphanol, meperidine, methadone, meptazinol, metopon,morphine, nalbuphine, nalorphine, oxycodone, papaveretum, pethidine,pentazocine, phenazocine, remifentanil, sufentanil, and tramadol.

Typically, where the drug is an other analgesic it is selected from oneof the following compounds: apazone, benzpiperylon, benzydramine,caffeine, clonixin, ethoheptazine, flupirtine, nefopam, orphenadrine,propacetamol, and propoxyphene.

Typically, where the drug is a stimulant, it is selected from one of thefollowing compounds: amphetamine, brucine, caffeine, dexfenfluramine,dextroamphetamine, ephedrine, fenfluramine, mazindol, methyphenidate,pemoline, phentermine, and sibutramine.

In a method aspect of the present invention, a method of forming a drugcontaining aerosol for use in inhalation therapy is provided. The methodincludes heating a substrate coated with a composition comprising a drugto form a vapor and mixing the vapor with a volume of air such that anaerosol having particles is formed. The mass median aerodynamic diameterof the formed particles is stable for at least 1 s.

Typically, the substrate is heated by moving it through a heating zone.Preferably, the heating zone is primarily produced by eddy currentsinduced by an alternating magnetic field.

Typically, the formed aerosol includes about 10⁹ particles/cc of air.

Typically, the drug of the composition is of one of the drugs or classesof drugs described above with respect to a device of the presentinvention.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features and advantages will become apparent from the followingdescription of various examples of the invention, as illustrated in theaccompanying drawings in which:

FIG. 1 is a schematic diagram of the overall system for conductingexperiments using a laboratory example of a device of the presentinvention;

FIG. 2 is a top, right end and front perspective view of the exampledepicted in FIG. 1;

FIG. 3 is a partial cross-sectional and partial schematic side view ofthe example shown in FIG. 2;

FIG. 4 is a partial cross-sectional and partial schematic end view ofthe example shown in FIG. 2;

FIG. 5 is a partial cross-sectional and partial schematic top view ofthe example shown in FIG. 2;

FIG. 6 is a schematic cross-sectional side view of an alternate exampleof the device of the present invention using an annunciating device;

FIG. 7 is a top, left end and front perspective views of the removablesub-assembly containing the compound and a movable slide of the exampleshown in FIG. 2 showing the sub-assembly being mounted within the slide;

FIG. 8 is a schematic view of the heating element of the example shownin FIG. 2 showing the electric drive circuit;

FIG. 9 is a schematic side view of a second example of the presentinvention using a venturi tube;

FIG. 10 is a schematic side view of a fourth example of the presentinvention using a thin-walled tube coated with the compound;

FIG. 11 is a schematic side end view of the example shown in FIG. 10;

FIG. 12 is a schematic side end view of the example shown in FIG. 10showing an inductive heating system generating an alternating magneticfield;

FIG. 13 is a schematic side view of an alternate example of that shownin FIG. 10 using a flow restrictor within the thin-walled tube;

FIG. 14 is a schematic side view of a fifth example of the presentinvention using an expandable container for the compound;

FIG. 15 is a schematic side view of a sixth example of the presentinvention using a container for the compound in an inert atmosphere;

FIG. 16 is a schematic side view of the example shown in FIG. 15 using are-circulation of the inert atmosphere over the compound's surface;

FIG. 17 is a schematic side view of a seventh example of the presentinvention using a tube containing particles coated with the compound;

FIG. 18 is a schematic side view of the example shown in FIG. 17 using aheating system to heat the gas passing over the coated particles;

FIG. 19 is a schematic side view of an eighth example of the presentinvention referred to herein as the “oven device”;

FIG. 20 is a schematic side view of an ninth example of the presentinvention using gradient heating;

FIG. 21 is a schematic side view of a tenth example of the presentinvention using a fine mesh screen coated with the compound;

FIG. 22 is a top, right end and front perspective view of the exampleshown in FIG. 21;

FIG. 23 is a plot of the rate of aggregation of smaller particles intolarger ones;

FIG. 24 is a plot of the coagulation coefficient (K) versus particlesize of the compound;

FIG. 25 is a plot of vapor pressure of various compounds, e.g., diphenylether, hexadecane, geranyl formate and caproic acid, versus temperature;

FIG. 26 is a plot of blood levels for both the IV dose and theinhalation dose administered to various dogs during the experimentsusing the system shown in FIG. 1;

FIG. 27 is a plot of calculated and experimental mass median diameter(MMD) versus compound mass in the range of 10 to 310 μg;

FIG. 28 is a plot of calculated and experimental MMD versus compoundmass in the range of 10 to 310 μg; and

FIG. 29 is a plot of the theoretical size (diameter) of an aerosol as afunction of the ratio of the vaporized compound to the volume of themixing gas.

DETAILED DESCRIPTION

Definitions

“Aerodynamic diameter” of a given particle refers to the diameter of aspherical droplet with a density of 1 g/mL (the density of water) thathas the same settling velocity as the given particle.

“Aerosol” refers to a suspension of solid or liquid particles in a gas.

“Decomposition index” refers to a number derived from an assay describedin Example 7. The number is determined by subtracting the percent purityof the generated aerosol from 1.

“Drug” refers to any chemical compound that is used in the prevention,diagnosis, treatment, or cure of disease, for the relief of pain, or tocontrol or improve any physiological or pathological disorder in humansor animals. Such compounds are oftentimes listed in the Physician's DeskReference (Medical Economics Company, Inc. at Montvale, N.J., 56^(th)edition, 2002), which is herein incorporated by reference.

Exemplary drugs include the following: cannabanoid extracts fromcannabis, THC, ketorolac, fentanyl, morphine, testosterone, ibuprofen,codeine, nicotine, Vitamin A, Vitamin E acetate, Vitamin E,nitroglycerin, pilocarpine, mescaline, testosterone enanthate, menthol,phencaramkde, methsuximide, eptastigmine, promethazine, procaine,retinol, lidocaine, trimeprazine, isosorbide dinitrate, timolol,methyprylon, etamiphyllin, propoxyphene, salmetrol, vitamin E succinate,methadone, oxprenolol, isoproterenol bitartrate, etaqualone, Vitamin D3,ethambutol, ritodrine, omoconazole, cocaine, lomustine, ketamine,ketoprofen, cilazaprol, propranolol, sufentanil, metaproterenol,prentoxapylline, testosterone proprionate, valproic acid, acebutolol,terbutaline, diazepam, topiramate, pentobarbital, alfentanil HCl,papaverine, nicergoline, fluconazole, zafirlukast, testosterone acetate,droperidol, atenolol, metoclopramide, enalapril, albuterol, ketotifen,isoproterenol, amiodarone HCl, zileuton, midazolam, oxycodone,cilostazol, propofol, nabilone, gabapentin, famotidine, lorezepam,naltrexone, acetaminophen, sumatriptan, bitolterol, nifedipine,Phenobarbital, phentolamine, 13-cis retinoic acid, droprenilamin HCl,amlodipine, caffeine, zopiclone, tramadol HCl, pirbuterol naloxone,meperidine HCl, trimethobenzamide, nalmefene, scopolamine, sildenafil,carbamazepine, procaterol HCl, methysergide, glutathione, olanzapine,zolpidem, levorphanol, buspirone and mixtures thereof.

Typically, the drug of the composition is of one of the followingclasses: antibiotics, anticonvulsants, antidepressants, antiemetics,antihistamines, antiparkisonian drugs, antipsychotics, anxiolytics,drugs for erectile dysfunction, drugs for migraine headaches, drugs forthe treatment of alcoholism, drugs for the treatment of addiction,muscle relaxants, nonsteroidal anti-inflammatories, opioids, otheranalgesics, cannabanoids, and stimulants.

Typically, where the drug is an antibiotic, it is selected from one ofthe following compounds: cefmetazole; cefazolin; cephalexin; cefoxitin;cephacetrile; cephaloglycin; cephaloridine; cephalosporins, such ascephalosporin C; cephalotin; cephamycins, such as cephamycin A,cephamycin B, and cephamycin C; cepharin; cephradine; ampicillin;amoxicillin; hetacillin; carfecillin; carindacillin; carbenicillin;amylpenicillin; azidocillin; benzylpenicillin; clometocillin;cloxacillin; cyclacillin; methicillin; nafcillin; 2-pentenylpenicillin;penicillins, such as penicillin N, penicillin O, penicillin S,penicillin V; chlorobutin penicillin; dicloxacillin; diphenicillin;heptylpenicillin; and metampicillin.

Typically, where the drug is an anticonvulsant, it is selected from oneof the following compounds: gabapentin, tiagabine, and vigabatrin.

Typically, where the drug is an antidepressant, it is selected from oneof the following compounds: amitriptyline, amoxapine, benmoxine,butriptyline, clomipramine, desipramine, dosulepin, doxepin, imipramine,kitanserin, lofepramine, medifoxamine, mianserin, maprotoline,mirtazapine, nortriptyline, protriptyline, trimipramine, viloxazine,citalopram, cotinine, duloxetine, fluoxetine, fluvoxamine, milnacipran,nisoxetine, paroxetine, reboxetine, sertraline, tianeptine,acetaphenazine, binedaline, brofaromine, cericlamine, clovoxamine,iproniazid, isocarboxazid, moclobemide, phenyhydrazine, phenelzine,selegiline, sibutramine, tranylcypromine, ademetionine, adrafinil,amesergide, amisulpride, amperozide, benactyzine, bupropion, caroxazone,gepirone, idazoxan, metralindole, milnacipran, minaprine, nefazodone,nomifensine, ritanserin, roxindole, S-adenosylmethionine, tofenacin,trazodone, tryptophan, venlafaxine, and zalospirone.

Typically, where the drug is an antiemetic, it is selected from one ofthe following compounds: alizapride, azasetron, benzquinamide,bromopride, buclizine, chlorpromazine, cinnarizine, clebopride,cyclizine, diphenhydramine, diphenidol, dolasetron methanesulfonate,dronabinol, droperidol, granisetron, hyoscine, lorazepam,metoclopramide, metopimazine, ondansetron, perphenazine, promethazine,prochlorperazine, scopolamine, triethylperazine, trifluoperazine,triflupromazine, trimethobenzamide, tropisetron, domeridone, andpalonosetron.

Typically, where the drug is an antihistamine, it is selected from oneof the following compounds: azatadine, brompheniramine,chlorpheniramine, clemastine, cyproheptadine, dexmedetomidine,diphenhydramine, doxylamine, hydroxyzine, cetrizine, fexofenadine,loratidine, and promethazine.

Typically, where the drug is an antiparkisonian drug, it is selected oneof the following compounds: amantadine, baclofen, biperiden,benztropine, orphenadrine, procyclidine, trihexyphenidyl, levodopa,carbidopa, selegiline, deprenyl, andropinirole, apomorphine,benserazide, bromocriptine, budipine, cabergoline, dihydroergokryptine,eliprodil, eptastigmine, ergoline pramipexole, galanthamine, lazabemide,lisuride, mazindol, memantine, mofegiline, pergolike, pramipexole,propentofylline, rasagiline, remacemide, spheramine, terguride,entacapone, and tolcapone.

Typically, where the drug is an antipsychotic, it is selected from oneof the following compounds: acetophenazine, alizapride, amperozide,benperidol, benzquinamide, bromperidol, buramate, butaperazine,carphenazine, carpipramine, chlorpromazine, chlorprothixene,clocapramine, clomacran, clopenthixol, clospirazine, clothiapine,cyamemazine, droperidol, flupenthixol, fluphenazine, fluspirilene,haloperidol, mesoridazine, metofenazate, molindrone, penfluridol,pericyazine, perphenazine, pimozide, pipamerone, piperacetazine,pipotiazine, prochlorperazine, promazine, remoxipride, sertindole,spiperone, sulpiride, thioridazine, thiothixene, trifluperidol,triflupromazine, trifluoperazine, ziprasidone, zotepine, zuclopenthixol,amisulpride, butaclamol, clozapine, melperone, olanzapine, quetiapine,and risperidone.

Typically, where the drug is an anxiolytic, it is selected from one ofthe following compounds: mecloqualone, medetomidine, metomidate,adinazolam, chlordiazepoxide, clobenzepam, flurazepam, lorazepam,loprazolam, midazolam, alpidem, alseroxlon, amphenidone, azacyclonol,bromisovalum, buspirone, calcium N-carboamoylaspartate, captodiamine,capuride, carbcloral, carbromal, chloral betaine, enciprazine,flesinoxan, ipsapiraone, lesopitron, loxapine, methaqualone, methprylon,propanolol, tandospirone, trazadone, zopiclone, and zolpidem.

Typically, where the drug is a drug for erectile dysfunction, it isselected from one of the following compounds: cialis (IC351),sildenafil, vardenafil, apomorphine, apomorphine diacetate,phentolamine, and yohimbine.

Typically, where the drug is a drug for migraine headache, it isselected from one of the following compounds: almotriptan, alperopride,codeine, dihydroergotamine, ergotamine, eletriptan, frovatriptan,isometheptene, lidocaine, lisuride, metoclopramide, naratriptan,oxycodone, propoxyphene, rizatriptan, sumatriptan, tolfenamic acid,zolmitriptan, amitriptyline, atenolol, clonidine, cyproheptadine,diltiazem, doxepin, fluoxetine, lisinopril, methysergide, metoprolol,nadolol, nortriptyline, paroxetine, pizotifen, pizotyline, propanolol,protriptyline, sertraline, timolol, and verapamil.

Typically, where the drug is a drug for the treatment of alcoholism, itis selected from one of the following compounds: naloxone, naltrexone,and disulfiram.

Typically, where the drug is a drug for the treatment of addiction it isbuprenorphine.

Typically, where the drug is a muscle relaxant, it is selected from oneof the following compounds: baclofen, cyclobenzaprine, orphenadrine,quinine, and tizanidine.

Typically, where the drug is a nonsteroidal anti-inflammatory, it isselected from one of the following compounds: aceclofenac, alminoprofen,amfenac, aminopropylon, amixetrine, benoxaprofen, bromfenac, bufexamac,carprofen, choline, salicylate, cinchophen, cinmetacin, clopriac,clometacin, diclofenac, etodolac, indoprofen, mazipredone,meclofenamate, piroxicam, pirprofen, and tolfenamate.

Typically, where the drug is an opioid, it is selected from one of thefollowing compounds: alfentanil, allylprodine, alphaprodine,anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol,carbiphene, cipramadol, clonitazene, codeine, dextromoramide,dextropropoxyphene, diamorphine, dihydrocodeine, diphenoxylate,dipipanone, fentanyl, hydromorphone, L-alpha acetyl methadol,lofentanil, levorphanol, meperidine, methadone, meptazinol, metopon,morphine, nalbuphine, nalorphine, oxycodone, papaveretum, pethidine,pentazocine, phenazocine, remifentanil, sufentanil, and tramadol.

Typically, where the drug is an other analgesic it is selected from oneof the following compounds: apazone, benzpiperylon, benzydramine,caffeine, clonixin, ethoheptazine, flupirtine, nefopam, orphenadrine,propacetamol, and propoxyphene.

Typically, where the drug is a cannabanoid, it is tetrahydrocannabinol(e.g., delta-8 or delta-9).

Typically, where the drug is a stimulant, it is selected from one of thefollowing compounds: amphetamine, brucine, caffeine, dexfenfluramine,dextroamphetamine, ephedrine, fenfluramine, mazindol, methyphenidate,pemoline, phentermine, and sibutramine.

“Drug degradation product” refers to a compound resulting from achemical modification of a drug. The modification, for example, can bethe result of a thermally or photochemically induced reaction. Suchreactions include, without limitation, oxidation and hydrolysis.

“Mass median aerodynamic diameter” or “MMAD” of an aerosol refers to theaerodynamic diameter for which half the particulate mass of the aerosolis contributed by particles with an aerodynamic diameter larger than theMMAD and half by particles with an aerodynamic diameter smaller than theMMAD.

“Stable aerosol” refers to an aerosol where the MMAD of its constituentparticles does not vary by more than 50% over a set period of time. Forexample, an aerosol with an MMAD of 100 nm is stable over 1 s, if at atime 1 second later it has an MMAD between 50 nm and 150 nm. Preferably,the MMAD does not vary by more than 25% over a set period of time. Morepreferably, the MMAD does not vary by more than 20%, 15%, 10% or 5% overtime.

Aerosolization Device

Example 1 is described in terms of an in vivo dog experiment. Theexample, however, is easily modified to suit human inhalation primarilythrough increasing airflow through it.

Referring to FIGS. 1-8, a first example (1) of an aerosolization deviceof the present invention will be described. The device 1 as shown inFIG. 1 is operably connected to flow meter 4 (e.g., a TSI 4100 flowmeter). The readings from flow meter 4 are fed to the electronics withinchassis 8 shown in FIG. 2. Flow meter 4 is shown in FIG. 1 within adotted line to indicate housing 10. Device controller 20 includesChembook model #N30W laptop computer having actuator switch 22 (FIG. 3)and National Instruments I/O Board (model #SC2345) (not shown) thatinterfaces with computer 20 to control device 1 and to control therecording of all data collected during the experiments. A softwareprogram to carry out these functions was developed using NationalInstruments' Labview software program.

Connection between device 1 and the I/O board is accomplished with acable (e.g., DB25, not shown). A standard power supply (e.g., CondorF15-15-A+ not shown) delivers power to device 1. Inhalation controller30 is used to control the rate and volume of inhalation through device 1into an anesthetized dog through an endotracheal tube 34. Controller 30has a programmable breath hold delay, at the end of which, exhaust valve40 in exhaust line 42 opens and the dog is allowed to exhale. Filter 50in line 42 measures the amount of exhaust and its composition to monitorany exhaled drug. The source air through inlet line 54, inlet valve 58,flow meter 4 and inlet orifice 59 is from a compressed air cylinder (notshown).

Now referring to FIGS. 3-5 and 7, a dose of compound 60 is depositedonto thin, stainless steel foil 64 so that the thickness of compound 60is less than 10 microns. In most cases, compound 60 is deposited bymaking a solution of the compound with an organic solvent. This mixtureis then applied to the foil substrate with an automated pump system. Asshown, the size of the entire foil 64 (e.g., alloy of 302 or 304 with0.004 in. thickness) is 0.7 by 2.9 inches and the area in which compound60 is deposited is 0.35 by 1.6 inches. Other foil materials can be usedbut stainless steel has an advantage over other materials like aluminumin that it has a much lower thermal conductivity value, while notappreciably increasing the thermal mass. A low thermal conductivity ishelpful because the heat generated in foil 64 should stay in the area ofinterest (i.e., the heating/vaporization zone 70). Foil 64 should have aconstant cross section, because otherwise the electrical currentsinduced by the heater will not be uniform. Foil 64 is held in frame 68,made so that the trailing edge of foil 64 has no lip on movable slide 78and so compound 60, once mixed with the air, is free in a downstreamdirection as indicated by arrow 127 of FIG. 3. Frame 68 is typicallymade of a non-conductive material to withstand moderate heat (e.g., 200°C.) and to be non-chemically reactive with the compound (e.g., DELRINAF®), a copolymer of acetal and TEFLON®).

Sub-assembly 80, shown in FIG. 7, consists of frame 68 having compound(60) coated foil 64 mounted therein. Sub-assembly 80 is secured withinmovable slide 78 by setting each of the downstream, tapered ends offrame 68 to abut against small rods 86 protruding from each downstreamend of slide 78, as shown in FIG. 7. Slide 78 is driven by stepper motor88, shown in FIG. 3, that moves sub-assembly 80 containing compound 60along the longitudinal axis of example 1. This, in turn, moves stainlesssteel foil 64 through an alternating magnetic field. (It is preferablefor the magnetic field to be confined within heating/vaporization zone70, shown in FIG. 5, as in this laboratory example.) Ferrite toroid 90is used to direct the magnetic field and is placed below foil 64 (e.g.,approximately 0.05 inches below). As shown in FIG. 5, heated area 70 isapproximately 0.15 by 0.4 inches, with the smaller dimension along thedirection of travel from left to right (i.e., from the upstream to thedownstream ends of device 1) and the large dimension across thedirection of travel (i.e., the width of device 1).

Foil 64 functions as both a substrate for the drug to be delivered tothe subject and the heating element for the vaporization of the drug.Heating element 64 is heated primarily by eddy currents induced by analternating magnetic field. The alternating magnetic field is producedin ferrite toroid 90 (e.g., from Fair-Rite Company) with slit 94 (e.g.,0.10 in. wide), which was wrapped with coil 98 of copper magnet wire.When an alternating current is passed through coil 98, an alternatingmagnetic field is produced in ferrite toroid 90. A magnetic field fillsthe gap formed by slit 94 and magnetic field fringe lines 100, shown inFIGS. 5 and 6, extend out from toroid 90. The magnetic field line fringelines 100 intersect heating element 64. When using a ferrite core, thealternating frequency of the field is limited to below 1 MHz. In thisdevice, a frequency between 100 and 300 kHz is typically used.

The location and geometry of the eddy currents determine where foil 64will be heated. Since magnetic field fringe lines 100 pass through foil64 twice, once leaving ferrite toroid 90 and once returning, two ringsof current are produced, and in opposite directions. One of the rings isformed around magnetic field lines 100 that leave toroid 90 and theother ring forms around magnetic field lines 100 that return toroid 90.The rings of current overlap directly over the center of slit 94. Sincethey were in opposite directions, they sum together. The greatestheating effect is therefore produced over the center of slit 94.

Slide 78 and its contents are housed in airway 102 made up of upperairway section 104 and lower airway section 108 shown in FIG. 3. Upperairway section 104 is removable and allows the insertion of movableslide 78, sub-assembly 80 and foil 64. Lower airway section 108 ismounted on top of chassis 8 that houses the electronics (not shown),magnetic field generator 110, stepper motor 88 and position sensors (notshown). Referring again to FIG. 1, mounted in upper airway section 104is upstream passage 120 and inlet orifice 59 that couples upper airwaysection 104 to flow meter 4. The readings from the flow meter 4 are fedto the electronics housed in chassis 8. Additionally, at the downstreamend of airway passage 102, outlet 124 is connected to mouthpiece 126.During administration of compound 60 to the dog, when joined to thesystem, air is forced through inlet line 54, flow meter 4, airway 102,and outlet 124 into the dog.

Additionally, a pyrometer at the end of TC2 line 130 is located withinairway 102 and is used to measure the temperature of foil 64. Because ofthe specific geometry of the example shown in FIGS. 1-7, the temperaturereading of foil 64 is taken after heating zone 70. Calibration of thethermal decay between heating zone 70 and the measurement area isrequired. Temperature data is collected and used for quality control andverification and not to control any heating parameters. A secondtemperature sensor is located at the end of TC1 line 132 in outlet 124and is used to monitor the temperature of the air delivered to the dog.

In a preferred example of the experimental device, removable block 140,mounted on upper airway section 104, restricts a cross-sectional area ofairway 102 and provides a specific mixing geometry therein. In thispreferred example, airway 140 lowers the roof of upper airway section104 (e.g., to within 0.04 inch of) with respect to foil 64.Additionally, block 140 contains baffles (e.g., 31 steel rods 0.04 in.in diameter, not shown). The rods are oriented perpendicular to the foiland extend from the top of upper airway section 104 to within a smalldistance of the foil (e.g., 0.004 in.). The rods are placed in astaggered pattern and have sharp, squared off ends, which causeturbulence as air passes around them. This turbulence assures completemixing of vaporized compounds with air passing through the device.

A second example (150) of an aerosolization device of the presentinvention, in which the cross-sectional area is also restricted alongthe gas/vapor mixing area, will be described in reference to FIG. 9. Inthis example, venturi tube 152 within housing 10 having inlet 154,outlet 156 includes a throat 158 between inlet 154 and outlet 156, whichis used to restrict the gas flow through venturi tube 152. Additionally,a controller 160 is designed to control the flow of air passing througha valve 164 based on readings from the thermocouple 168 of thetemperature of the air, which can be controlled by heater 166.

Block 140 is located directly over heating zone 70 and creates aheating/vaporization/mixing zone. Prior to commencing aerosolgeneration, slide 78 is in the downstream position. Slide 78, with itscontents, is then drawn upstream into this heating/vaporization/mixingzone 70 as energy is applied to foil 64 through the inductive heatersystem described in detail below.

The device of the present invention is optionally equipped with anannunciating device. One of the many functions for the annunciatingdevice is to alert the operator of the device that a compound is notbeing vaporized or is being improperly vaporized. The annunciatingdevice can also be used to alert the operator that the gas flow rate isoutside a desired range. FIG. 6 is a schematic diagram illustrating athird example of a hand held aerosolization device 180 of the presentinvention. As shown, device 180 includes many of the components ofdevice 150, discussed above, and additionally includes an annunciatingdevice 170. During the use of device 180 in which the patient'sinhalation rate controls the airflow rate, a signal from annunciatingdevice 170 would alert the patient to adjust the inhalation rate to thedesired range. In this case, controller 160 would be connected toannunciating device 170 to send the necessary signal that the flow ratewas not within the desired range.

The induction drive circuit 190 shown in FIG. 8 is used to drive theinduction-heating element of device 1. The purpose of circuit 190 is toproduce an alternating current in drive coil 98 wrapped around ferritecore 90. Circuit 190 consists of two P-channel transistors 200 and twoN-channel MOSFET transistors 202 arranged in a bridge configuration.MOSFET transistors 200 and 202 connected to clock pulse generator 219are turned on and off in pairs by D-type flip-flop 208 through MOSFETtransistor drive circuit 210. D-type flip-flop 208 is wired to cause theQ output of the flip-flop to alternately change state with the risingedge of the clock generation signal. One pair of MOSFET transistors 200is connected to the Q output on D-type flip-flop 208 and the other pair,202, is connected to the Q-not output of flip-flop 208. When Q is high(5 Volts), a low impedance connection is made between the D.C. powersupply (not shown) and the series combination of drive coil 98 and thecapacitor through the pair of MOSFET transistors 200 controlled by the Qoutput. When D-type flip-flop 208 changes state and Q-not is high, thelow impedance connection from the power supply to the series combinationdrive coil 98 and capacitor 220 is reversed. Since flip-flop 208 changesstate on the rising edge of the clock generation signal, two flip-flopchanges are required for one complete drive cycle of theinduction-heating element. The clock generation signal is typically setat twice the resonant frequency of the series combination of drive coil90 and capacitor 220. The clock signal frequency can be manually orautomatically set.

A second example (150) of an aerosolization device of the presentinvention, in which the cross-sectional area is also restricted alongthe gas/vapor mixing area, will be described in reference to FIG. 9. Inthis example, venturi tube 152 within housing 10 having inlet 154,outlet 156 and throat 158 between inlet 154 and outlet 156 is used torestrict the gas flow through venturi tube 152. Controller 160 isdesigned to control the flow of air passing through valve 164 based onreadings from the thermocouple 168 of the temperature of the air as aresult of heater 166.

A fourth example (300) of an aerosolization device of the presentinvention will be described in reference to FIGS. 10 and 11. A gasstream is passed into thin walled tube 302 having a coating (310) ofcompound 60 on its inside. The flow rate of the gas stream is controlledby valve 314. The device of example 300, as with others, allows forrapid heat-up using a resistive heating system (320) while controllingthe flow direction of vaporized compound. After activating heatingsystem 320 with actuator 330, current is passed along tube 302 in theheating/vaporization zone 340 as the carrier gas (e.g., air, N₂ and thelike) is passed through tube 302 and mixes with the resulting vapor.

FIG. 12 shows an alternative heating system to resistive heating system320 used in connection with the fourth example. In this case, inductiveheating system 350 consists of a plurality of ferrites 360 forconducting the magnetic flux to vaporize compound 310.

FIG. 13 shows a variation on the fourth example in which flow restrictor370 is mounted within thin-walled tube 302 by means of support 374within a housing (not shown) to increase the flow of mixing gas acrossthe surface of compound 310.

A fifth example 400 of an aerosolization device of the present inventionwill be described in reference to FIG. 14. For this example, compound 60is placed within expandable container 402 (e.g., a foil pouch) and isheated by resistance heater 406, which is activated by actuator 410 asshown in FIG. 14. The vaporized compound generated is forced intocontainer 420 through outlet passage 440 and mixed with the gas flowingthrough tube 404. Additional steps are taken, when necessary, topreclude or retard decomposition of compound 60. One such step is theremoval or reduction of oxygen around 60 during the heat up period. Thiscan be accomplished, for example, by sealing the small container housingin an inert atmosphere.

A sixth example 500 of an aerosolization device of the present inventionwill be described in reference to FIG. 15. Compound 60 is placed in aninert atmosphere or under a vacuum in container 502 within housing 10and is heated by resistance heater 504 upon being activated by actuator508 as shown in FIG. 15. Once compound 60 has become vaporized it canthen be ejected through outlet passage 510 into the air stream passingthrough tube 520.

FIG. 16 shows a variation of device 500 in which fan 530 recirculatesthe inert atmosphere over the surface of compound 60. The inert gas froma compressed gas cylinder (not shown) enters through inlet 540 andone-way valve 550 and exits through outlet passage 510 into tube 502.

A seventh example (600) of an aerosolization device of the presentinvention will be described in reference to FIG. 17. A compound (notshown), such as compound 60 discussed above, is deposited onto asubstrate in the form of discrete particles 602 (e.g., aluminum oxide(alumina), silica, coated silica, carbon, graphite, diatomaceous earth,and other packing materials commonly used in gas chromatography). Thecoated particles are placed within first tube 604, sandwiched betweenfilters 606 and 608, and heated by resistance heater 610, which isactivated by actuator 620. The resulting vapor from tube 604 is combinedwith the air or other gas passing through second tube 625.

FIG. 18 shows a variation of device 600 in which resistance heater 630heats the air prior to passing through first tube 604 and over discreteparticles 602.

An eighth example 700 of an aerosolization device of the presentinvention will be described in reference to FIG. 19. Compound 60 isdeposited into chamber 710 and is heated by resistance heater 715, whichis activated by actuator 720. Upon heating, some of compound 60 isvaporized and ejected from chamber 710 by passing an inert gas enteringhousing 10 through inert gas inlet 725 and valve 728 across the surfaceof the compound. The mixture of inert gas and vaporized compound passesthrough passage 730 and is then mixed with a gas passing through tube735.

A ninth example 800 of an aerosolization device of the present inventionwill be described in reference to FIG. 20. Thermally conductivesubstrate 802 is heated by resistance heater 810 at the upstream end oftube 820, and the thermal energy is allowed to travel along substrate802. This produces, when observed in a particular location, a heat uprate that is determined from the characteristics of the thermallyconductive substrate. By varying the material and its cross sectionalarea, it was possible to control the rate of heat up. The resistiveheater is embedded in substrate 802 at one end. However, it could beembedded into both ends, or in a variety of positions along thesubstrate and still allow the temperature gradient to move along thecarrier and/or substrate.

A tenth example 900 of an aerosolization device of the present inventionwill be described in reference to FIGS. 21 and 22. Air is channeledthrough a fine mesh metal screen 902 on which drug is deposited. Screen902 is positioned across airway passage 910 (e.g., constructed from 18mm glass tubing). The two sides of the screen are electrically connectedto charged capacitor 920 through silicon-controlled rectifier (SCR) 922to make a circuit. The charge of the capacitor is calculated and set ata value such that, when actuator 930 closes SCR 922, the energy fromcapacitor 920 is converted to a desired temperature rise in screen 902.

General Considerations

The device of the present invention utilizes a flow of gas (e.g., air)across the surface of a compound (60) to sweep away vaporized molecules.This process drives vaporization as opposed to condensation andtherefore enables aerosol formation at relatively moderate temperatures.Nicotine (1 mg, by 247° C./745 mm), for example, vaporized in less than2 s at about 130° C. in a device of the present invention. Similarly,fentanyl (bp>300° C./760 mm) was vaporized around 190° C. in quantitiesup to 2 mg.

Purity of an aerosol produced using a device of the present invention isenhanced by limiting the time during which a compound (60) is exposed toelevated temperatures. This is accomplished by rapidly heating a thinfilm of the compound to vaporize it. The vapors are then immediatelycooled upon entry into a carrier gas stream.

Typically, compound 60 is subjected to a temperature rise of at least1,000° C./second. In certain cases, the compound is subjected to atemperature rise of at least 2,000° C./second, 5,000° C./second, 7,500°C. or 10,000° C./second. A rapid temperature rise within the compound isfacilitated when it is coated as a thin film (e.g., between 10μ and 10nm in thickness). The compound is oftentimes coated as a film between 5μand 10 nm, 4μ and 10 nm, 3μ and 10 nm, 2μ and 10 nm, or even 1μ to 10 nmin thickness.

Rapid temperature rises and thin coatings ensure that compounds aresubstantially vaporized in a short time. Typically, greater than 0.1 mg,0.25 mg, 0.5 mg, 0.75 mg or 1 mg of a compound is vaporized in less than100 milliseconds from the start of heating. Oftentimes, the same amountof compound is vaporized in less than 75 milliseconds, 50 milliseconds,25 milliseconds, or 10 milliseconds from the start of heating.

Examples of compounds that have benefited from rapid heating in a deviceof the present invention include lipophilic substance #87 and fentanyl.Lipophilic substance #87 decomposed by more than 90% when heated at 425°C. for 5 minutes, but only 20% when the temperature was lowered to 350°C. Decomposition of the substance was further lowered to about 12% whenthe heating time was decreased to 30 seconds and to less than 2% at10-50 milliseconds. A fentanyl sample decomposed entirely when heated to200° C. for 30 seconds, and only 15-30% decomposed when heated for 10milliseconds. Vaporizing fentanyl in device 1 led to less than 0.1%decomposition.

An aerosol of the present invention contains particles having an MMADbetween 10 nm and 1μ, preferably 10 nm to 900 nm, 10 nm to 800 nm, 10 nmto 700 nm, 10 nm to 600 nm, 10 nm to 500 nm, 10 nm to 400 nm, 10 nm to300 nm, 10 nm to 200 nm, or 10 nm to 100 nm. Particles are produced suchthat their size is stable for several seconds (e.g., 1 to 3 s). Theaerosol particle size and subsequent stability is controlled by the rateof compound vaporization, the rate of carrier gas introduction, and themixing of resultant vapors and the carrier gas. Such control isaccomplished using a number of methods, including the following: (a)measuring the quantity and regulating the flow rate of the mixing air;and/or, (b) regulating the vaporization rate of the compound (e.g., bychanging the energy transferred to the compound during the heatingprocess or changing the amount of compound introduced into a heatingregion).

A desired particle size is achieved by mixing a compound in its vaporstate into a volume of a carrier gas in a ratio such that, when thenumber concentration of the mixture reaches approximately 10⁹particles/mL, a particle that exists in a size range from 10 nm to 100nm for 1 to 3 seconds results.

FIG. 23 is a plot of theoretical data calculated from a mathematicalmodel. See “Aerosol Technology” W. C. Hinds, second edition 1999, Wiley,New York. It shows the time in seconds it takes for the numberconcentration of an aerosol to aggregate to half of its original valueas a function of the particle concentration. For example, a 1.0 mgvaporized dose of a compound with a molecular weight of 200 that ismixed into 1 liter of air will have approximately 3×10¹⁸ molecules(particles) in the liter. This results in a number concentration of3×10¹⁵/cc. Extrapolating from FIG. 23, one can see that it takes lessthan 10 milliseconds for the number of particles to halve in thisexample. Therefore, to insure uniform mixing of a vaporized compound,the mixing must occur in a very short time. FIG. 23 also shows that whenthe number concentration of the mixture reaches approximately 10⁹particles/cc, the particle size is “stable” for the purpose of drugdelivery by inhalation.

FIG. 23 is for an aerosol having a Coagulation Coefficient (K) of5×10⁻¹⁶ meters³/second. This K value corresponds to a particle size of200 nm. As the particle size changes, so can its K value. Table 1 belowgives the K values for various particle sizes. As K increases, the timerequired for the aerosol to aggregate from a particular particle size toa larger particle size is reduced. As can be seen from Table 1 and FIG.24, when the particle is in the 10 nm to 100 nm range, the effect of achanging K value tends to accelerate the coagulation process towards 100nm in size.

TABLE 1 Coagulation Particle size Coefficient (× e⁻¹⁵ (diameter in nm)meters³/second) 1 3.11 5 6.93 10 9.48 20 11.50 50 9.92 100 7.17 200 5.09500 3.76 1000 3.35 2000 3.15 5000 3.04 10000 3.00

In creating an aerosol of a particular particle size, the ratio of massof vaporized compound to the volume of the mixing gas is the controllingcondition. By changing this ratio, the particle size can be manipulated(see FIG. 29). However, not all compounds and not all gases, with thesame ratio will result in the same particle size distribution (PSD).Other factors must be known to be able to accurately predict theresultant particle size. A compound's density, polarity, and temperatureare examples of some of these factors. Additionally, whether thecompound is hydrophilic or hydrophobic will affect the eventual particlesize, because this factor affects an aerosol's tendency to grow bytaking on water from the surrounding environment.

In order to simplify the approach used to predict the resulting particlesize, the following assumptions were made:

-   -   1. The compound is non polar (or has a weak polarity).    -   2. The compound is hydrophobic or hydrophilic with a mixing gas        that is dry.    -   3. The resultant aerosol is at or close to standard temperature        and pressure.    -   4. The coagulation coefficient is constant over the particle        size range and therefore the number concentration that predicts        the stability of the particle size is constant.

Consequently, the following variables are taken into consideration inpredicting the resulting particle size:

-   -   1. The amount (in grams) of compound vaporized.    -   2. The volume of gas (in cc's) that the vaporized compound is        mixed into.    -   3. The “stable” number concentration in number of particles/cc.    -   4. The geometric standard deviation (GSD) of the aerosol.

Where the GSD is 1, all of the particle sizes are the same size andtherefore the calculation of particle size becomes a matter of dividinga compound's mass into the number of particles given by the numberconcentration and from there calculating the particle size diameterusing the density of the compound. The problem becomes different,though, if the GSD is other than 1. As an aerosol changes from a GSD of1 to a GSD of 1.35, the mass median diameter (MMD) will increase. MMD isthe point of equilibrium where an equal mass of material exists insmaller diameter particles as exists in larger diameter particles. Sincetotal mass is not changing as the GSD changes, and since there are largeand small particles, the MMD must become larger as the GSD increasesbecause the mass of a particle goes up as the cube of its diameter.Therefore larger particles, in effect, carry more weight and the MMDbecomes larger to “balance” out the masses.

To determine the effect of a changing GSD, one can start with theformula for the mass per unit volume of an aerosol given a known MMD,GSD, density, and number concentration. The formula is from Finlay's“The Mechanics of Inhaled Pharmaceutical Aerosols” (2001, Academicpress). Formula 2.39 states that the mass per unit volume of an aerosolis:M=(ρNπ/6)(MMD)³exp[−9/2(ln σ_(g)) ^(2])

-   -   Where:    -   ρ=density in gm/cc    -   N=Number concentration in particles/cc    -   MMD=mass median diameter (in cm)    -   σ_(g)=the GSD    -   M=the mass per unit volume of the aerosol in gms/cc

If the change in the MMD is considered as an aerosol changes from oneGSD to another, while the density, number concentration, and the massremain unchanged the following equality can be set up:σ_(g) Nπ/6(MMD₁)³exp[−9/2(ln σ_(g1))²]=ρNπ/6(MMD₂)³exp[−9/2(ln σ_(g2))²]simplifying:(MMD₁)³exp[−9/2(ln σ_(g1))²]=(MMD₂)³exp[−9/2(ln σ_(g2))²]Or(MMD₁)³/(MMD₂)³=exp[−9/2(ln σ_(g2))²]/exp[−9/2(ln σ_(g1))²]

If one sets the GSD of case 1 to 1.0 then:exp[−9/2(ln σ_(g1))²=1And therefore:(MMD₁/MMD₂)³=exp[−9/2(ln σ_(g2))²]Or:MMD₁/MMD₂=exp[−3/2(ln σ_(g2))²]

It is advantageous to calculate the change in the MMD as the GSDchanges. Solving for MMD₂ as a function of MMD₁ and the new GSD₂ yields:MMD₂=MMD₁/exp[−3/2(ln σ_(g2))²] for a σ_(g1)=1

To calculate MMD₁, divide the compound's mass into the number ofparticles and then, calculate its diameter using the density of thecompound.MMD₁=(6C/ρNV)^(1/3) for an aerosol with a GSD of 1

-   -   Where:    -   C=the mass of the compound in gm's    -   ρ=Density in gm/cc (as before)    -   N=Number concentration in particles/cc (as before)    -   V=volume of the mixing gas in cc

Insertion of MMD₁ into the above equation leads to:MMD₂=(6C/ρNVπ)^(1/3)/[exp[−3/2(ln σ_(g2))²], measured in centimeters.

A resultant MMD can be calculated from the number concentration, themass of the compound, the compound density, the volume of the mixinggas, and the GSD of the aerosol.

The required vaporization rate depends on the particle size one wishesto create. If the particle size is in the 10 nm to 100 nm range,then-the compound, once vaporized, must be mixed, in most cases, intothe largest possible volume of air. This volume of air is determinedfrom lung physiology and can be assumed to have a reasonable upper limitof 2 liters. If the volume of air is limited to below 2 liters (e.g.,500 cc), too large a particle will result unless the dose is exceedinglysmall (e.g., less than 50 μg).

In the 10 nm to 100 nm range, doses of 1-2 mg are possible. If this doseis mixed into 2 liters of air, which will be inhaled in 1-2 seconds, therequired, desired vaporization rate is in the range of about 0.5 toabout 2 mg/second.

The first example of the present invention is shown in FIG. 1 and is thebasic device through which the principles cited above have beendemonstrated in the laboratory. This device is described in detail inthe EXAMPLES.

In the second example of the present invention shown in FIG. 9, the useof a reduced airway cross section increases the speed of the air acrossthe compound's surface to about 10 meters/second. If complete mixing isto happen within 1 millisecond, then the distance the gas and vaporizedmixture must travel to achieve complete mixing must be no longer than 10millimeters. However, it is more desirable for complete mixing to happenbefore the compound has aggregated to a larger size, so a desirablemixing distance is typically about 1 millimeter or less.

In the fourth example of the present invention shown in FIGS. 10-13, anaerosol having particles with an MMAD in the 10 nm to 100 nm range isgenerated by allowing air to sweep over a thin film of the compoundduring the heating process. This allows the compound to become vaporizedat a lower temperature due to the lowering of the partial pressure ofthe compound near the surface of the film.

The fifth example shown in FIG. 14, the sixth example shown in FIGS. 15and 16, and the eighth example shown in FIG. 19 overcome a problem withcertain compounds that react rapidly with oxygen at elevatedtemperatures. To solve this problem, the compound is heated in anexpandable container (fourth example), a small container housing under avacuum or containing a small amount, e.g., about 1 to about 10 ml, of aninert gas (fifth example). Once a compound is vaporized and mixed withan inert gas while the gaseous mixture is maintained at a temperaturesufficient to keep the compound in its vaporized state, the gaseousmixture is then injected into an air stream. The volume of inert gas canalso be re-circulated over the surface of the heated compound to aid inits vaporization as shown in FIG. 16. In the seventh example, thecompound is introduced into the gas as a pure vapor. This involvesvaporizing the compound in an oven or other container and then injectingthe vapor into an air or other gas stream through one or more mixingnozzles.

In the sixth example shown in FIGS. 17-18, gas is passed through a firsttube and over discrete substrate particles, having a large surface areato mass ratio, and coated with the compound. The particles are heated asshown in FIG. 17 to vaporize the compound, or the gas is heated and theheated gas vaporizes the compound as shown in FIG. 18. The gaseousmixture from the first tube is combined with the gas passing throughsecond tube to rapidly cool the mixture before administering it to apatient.

The eighth example shown in FIG. 20 is a thermal gradient device that issimilar to device 1 used in the laboratory experiments. This examplealso has a moving heating zone without any moving parts, accomplished byestablishing a heat gradient that transverses from one end of the deviceto the other over time. As the heating zone moves, exposed portions ofthe compound are sequentially heated and vaporized. In this manner thevaporized compound can be introduced into a gas stream over time.

The ninth example shown in FIGS. 21-22 is the screen device and ispreferred for generating a aerosols containing particles with an MMADgreater than 100 nm. In this example, air is channeled through a finemesh screen upon which the drug to be administered to the patient hasbeen deposited.

The examples above can create aerosols without significant drugdecomposition. This is accomplished while maintaining a requiredvaporization rate for particle size control by employing a shortduration heating cycle. An airflow over the surface of the-compound isestablished such that when the compound is heated and reaches thetemperature where vaporization is first possible, the resulting compoundvapors will immediately cool in the air. In the preferred examples, thisis accomplished by extending the increased velocity and mixing regionover an area that is larger than the heating zone region. As a result,precise control of temperature is not necessary since the compoundvaporizes the instant its vaporization temperature is reached.Additionally because mixing is also present at the point ofvaporization, cooling is accomplished quickly upon vaporization.

Application of the present invention to human inhalation drug deliverymust accommodate constraints of the human body and breathing physiology.Many studies of particle deposition in the lung have been conducted inthe fields of public health, environmental toxicology and radiationsafety. Most of the models and the in vivo data collected from thosestudies, relate to the exposure of people to aerosols homogeneouslydistributed in the air that they breathe, where the subject does nothingactively to minimize or maximize particle deposition in the lung. TheInternational Commission On Radiological Protection (ICRP) models areexamples of this. (See James A C, Stahlhofen W, Rudolph G, Egan M J,Nixon W, Gehr P, Briant J K, The respiratory tract deposition modelproposed by the ICRP Task Group. Radiation Protection Dosimetry, 1991;vol. 38: pgs. 157-168).

However, in the field of aerosol drug delivery, a patient is directed tobreathe in a way that maximizes deposition of the drug in the lung. Thiskind of breathing usually involves a full exhalation, followed by a deepinhalation sometimes at a prescribed inhalation flow rate range, e.g.,about 10 to about 150 liters/minute, followed by a breath hold ofseveral seconds. In addition, ideally, the aerosol is not uniformlydistributed in the air being inhaled, but is loaded into the early partof the breath as a bolus of aerosol, followed by a volume of clean airso that the aerosol is drawn into the alveoli and flushed out of theconductive airways, bronchi and trachea by the volume of clean air thatfollows. A typical deep adult human breath has a volume of about 2 to 5liters. In order to ensure consistent delivery in the whole populationof adult patients, delivery of the drug bolus should be completed in thefirst 1-1½ liters or so of inhaled air.

As a result of the constraints of human inhalation drug delivery, acompound should be vaporized in a minimum amount of time, preferably nogreater than 1 to 2 seconds. As discussed earlier, it is alsoadvantageous, to keep the temperature of vaporization at a minimum. Inorder for a compound to be vaporized in 2 seconds or less and for thetemperature to be kept at a minimum, rapid air movement, in the range ofabout 10 to about 120 liters/minute, should flow across the surface ofthe compound.

The following parameters are optimal in using a device of the presentinvention, due to human lung physiology, the physics of particle growth,and the physical chemistry of the desirable compounds:

-   -   (1) The compound should to be vaporized over approximately 1 to        2 seconds for creation of particles in the ultra fine range.    -   (2) The compound should to be raised to the vaporization        temperature as rapidly as possible.    -   (3) The compound, once vaporized, should be cooled as quickly as        possible.    -   (4) The compound should be raised to the maximum temperature for        a minimum duration of time to minimize decomposition.    -   (5) The air or other gas should be moved rapidly across the        surface of the compound to achieve the maximum rate of        vaporization.    -   (6) The heating of the air or other gas should be kept to a        minimum, i.e., an increase of temperature of no greater than        about 15° C. above ambient.    -   (7) The compound should be mixed into the air or other gas at a        consistent rate to have a consistent and repeatable particle        size.    -   (8) As the gas speed increases across the compound being        vaporized, the cross sectional area through the device should        decrease. Furthermore, as the surface area of the compound        increases the heating of the gas increases.

The parameters of the design for one of the examples shown in FIGS. 2-5,7 and 8 are the result of meeting and balancing the competingrequirements listed above. One especially important requirement for anaerosol containing particles with an MMAD between 10 nm and 100 nm isthat a compound, while needing to be vaporized within at least a1-second period, also needs to have each portion of the compound exposedto a heat-up period that is as brief as possible. In this example, thecompound is deposited onto a foil substrate and an alternating magneticfield is swept along a foil substrate heating the substrate such thatthe compound is vaporized sequentially over no more than about a onesecond period of time. Because of the sweeping action of the magneticfield, each segment of the compound has a heat-up time that is much lessthan one second.

In the example noted directly above, the compound is laid down on a thinmetallic foil. In one of the examples set forth below, stainless steel(alloy of 302, 304, or 316) was used in which the surface was treated toproduce a rough texture. Other foil materials can be used, but it isimportant that the surface and texture of the material is such that itis “wetted” by the compound when the compound is in its liquid phase,otherwise it is possible for the liquid compound to “ball” up whichwould defeat the design of the device and significantly change thevolatilizing parameters. If the liquid compound “balls” up, the compoundcan be blown into and picked up by the airflow without ever vaporizing.This leads to delivery of a particle size that is uncontrolled andundesirable.

Stainless steel has advantages over materials like aluminum because ithas a lower thermal conductivity value, without an appreciable increasein thermal mass. Low thermal conductivity is helpful because heatgenerated by the process needs to remain in the immediate area ofinterest.

EXAMPLES

The following examples further illustrate the method and variousexamples of the present invention. These examples are for illustrativepurposes and are not meant to limit the scope of the claims in any way.

Example 1 In Vivo Results Using Example 1

In this example, example 1, was designed to deliver an experimental doseof fentanyl between 20 μg and 500 μg, in a range of ultra fine particlesizes, in about 800 cc of air to a 10 kg dog. The lung volume of eachdog under experimentation was approximately 600-700 cc and the devicewas designed to deliver the compound to the lung in the first half ofthe inhalation. Because of the value of these parameters, device 1 inthis experiment can be considered a ¼ scale device for administering adose to a human. It is believed that scaling the device to work forhuman subjects involves mainly increasing the airflow through thedevice. The time frame of the introduction of the compound into theheating/vaporization/mixing zone was set such that the compoundvaporized into a volume of air that was suitable for both the volumerequired by dog lung anatomy (600-700 cc) and the volume needed tocontrol the ratio of the compound to the air.

The following was the sequence of events that took place during eachoperation:

-   -   1. At the beginning of the run, the operator triggered        inhalation controller 30 to start monitoring data from pressure        transducer 240 and input flow meter 4.    -   2. Controller 30 signaled controller 20 to start example 1 and        to begin collecting data from the two temperature sensors and        flow meter 4.    -   3. After a pre-programmed delay, example 1 initiated the        generation of the aerosol. (Note: there was a delay of about 0.4        seconds between the start of the controller 30 and the start of        aerosol generation.)    -   4. After an independent preprogrammed delay (from original        trigger signal), controller 30 opened input valve 58 to start        forced inhalation to a dog under experimentation.    -   5. Example 1 completed the aerosol generation during the        inhalation.    -   6. Controller 30 monitored flow meter 4 and pressure transducer        240 throughout the inhalation and closed off flow-at input valve        58 when a pre-specified volume or pressure was met. (Note: the        pre-specified pressure is a safety feature to prevent injury to        the subject animal. Termination of the breath at the        pre-specified volume is the desirable occurrence of the        experiment.)    -   7. After a breath hold delay (5 seconds), exhaust valve 40 was        opened and the dog was allowed to exhale.    -   8. Exhaled aerosol was trapped on exhaust filter 40 for later        analysis. Controller 30 recorded values for the following:        volume dispensed, terminal pressure, duration of air pulse, and        average flow rate. Controller 20 continuously recorded at        millisecond resolution, input flow rate, exhaust flow rate, foil        temperature, mouthpiece temperature, slide position, heater        on/off time, and other internal diagnostic electrical        parameters.

Three weight-matched female beagle dogs received fentanyl at a 100 μgintravenous bolus dose. The same dogs received fentanyl UF forInhalation (100 μg aerosolized and administered as two successiveactivations of device 1, containing approximately 50 μg fentanyl base)at a particle size of 80 nm (MMAD). The aerosol was administered toanesthetized dogs via the system schematically represented in FIG. 1,with a target delivered volume of 600-700 ml air, followed by a 5 secondbreath hold. After dosing, plasma samples for pharmacokinetic analysiswere obtained at various time points from 2 min to 24 hr. Fentanylremaining in device 1 was recovered and measured. Fentanylconcentrations were measured by using a validated GC method, with alimit of detection of 0.2 ng/ml.

Plasma pharmacokinetics from this example were compared to intravenous(IV) fentanyl (100 μg) in the same dogs. Inhalation of fentanyl resultedin rapid absorption (C_(max), maximum concentration in plasma, 11.6ng/ml and T_(max), maximum time, 2 min.) and high bioavailability (84%).The time course of inhaled fentanyl was nearly identical to that of IVfentanyl. Thus, fentanyl UF for inhalation had an exposure profile thatwas similar to that of an IV injection.

Standard non-compartmental pharmacokinetic methods were used tocalculate pharmacokinetic parameters for each animal. The maximumconcentration in plasma (C_(max)) and the maximum time it occurred(T_(max)) were determined by examination of the data. The area under theplasma concentration vs. time curve (AUC) was determined. Thebioavailability (F) of inhaled fentanyl was determined as:F=(DIV/DINHAL)*(AUCINHAL/AUCIV)

where D was the dose and AUC was the AUC determined to the lastmeasurable time point.

FIG. 26 plots the data obtained on the blood levels, by dog, for boththe IV doses and the inhalation doses using device 1 as described aboveunder Example 1.

The fentanyl aerosol was rapidly absorbed, with the same T_(max) (2 min,the earliest time point) observed for both routes of administration. Themaximum plasma concentration of fentanyl aerosol (11.6±1.9 ng/ml) wasnearly two-thirds that of IV fentanyl (17.6±3.6 ng/ml). Plasmaconcentrations fell below the assay limit of quantitation by 6-8 hrafter IV administration and by 3-4 hr after aerosol inhalation.Bioavailability calculations were based on the AUC's observed to thelast measurable time point for the inhalation administration.Bioavailability for the inhalation study was 84% based on the nominal(uncorrected) fentanyl dose.

The mean plasma elimination half-life was similar after IV (75.4 min)and inhalation dose. Distribution phase half-lives (3-4 min) were alsosimilar after both routes of administration. The inter-animalvariability of pharmacokinetic parameters after the inhalation dose waslow, with relative standard deviations (RSD<25%) lower than thoseobserved for IV administration.

Example 2 In Vitro Results Using Example 1

Table 2 below summarizes the data collected from use of example 1 for invitro testing of fentanyl. Particle size was measured with a Moudicascade impactor.

TABLE 2 Compound Mass (ug) Mixing air volume (cc) MMAD (nm) GSD 20 40071 1.9 25 400 72-78 1.7-1.8 50 400 77-88  1.7-185 100 400 100-1051.4-1.8 200 400 103-123 1.6-1.9 300 400 140-160 1.8-2.1

Example 3 Use of Example 1 to Make Fine Aerosol Particles

In this example, example 1 was slightly modified and the flow ratechanged, as discussed below, to make a fine aerosol in the 1 to 3 micronparticle size range.

Airway section 140 was removed and the air channel heating/vaporizationzone 70 was changed. An airway insert (not shown) had a “roof” that was0.25 inches above the foil. There were no mixing rods as rapid mixingwas not desirable in this example. Because of these two device changes,there was much less mixing with the air, thus the vapor/aerosol cloudwas mixed with less air and produced a larger particle size aerosol. Theairflow rate was reduced 1 liter/minute in this example. Again, thisallowed the vapor to be mixed with much less air, resulting in thelarger particle size aerosol.

Some operational problems with high compound loading on foil 64 inexample 1 were encountered. The compound tested, dioctyl phthalate(DOP), was an oil and during the aerosolization process, a substantialquantity was blown downwind and not aerosolized. Three additional designalternatives were made to address this issue, involving changes to thesubstrate surface that the compound was deposited on. In the threealternatives, the substrate was made to “hold” the compound through theuse of texture. They were: a) texturing the foil; b) adding a stainlesssteel screen on top of the foil; and, c) replacing the foil with a finestainless steel screen.

The results from this example are set forth below in Table 3 below:

TABLE 3 MMAD, Emitted Substrate Type microns GSD Dose, ug Textured foil1.49 microns 1.9 97 Textured foil 2.70 microns 1.95 824 Fine screenalone 1.59 microns 1.8 441 Fine screen alone 1.66 microns 1.8 530 Screenon Foil 2.42 microns 2.2 482

As shown above, a fine particle size can be made with device 1 merely bychanging the ratio of the compound to the mixing air.

Example 4 In Vitro Results Using Example 700

A tank was partially filled with DOP and placed inside an oven (notshown) having an inlet and an outlet. DOP was used as the test compound.The tank was purged with helium prior to heating the tank and itscontents to a temperature of 350° C. Helium was pumped through the tankand used to carry the DOP vapor out of the outlet. The gaseous mixtureof helium and vaporized compound 60 was introduced into different sizemixing tubes through a nozzle. Each of the tubes had air moving throughthem at 14 liters/minute. The nozzle was perpendicular to the flowdirection. After this gaseous mixture was mixed with the air, theresulting aerosol was introduced into a parallel flow diffusion batteryfor particle size analysis. Results are set forth in Table 4 below.

TABLE 4 Mixing tube size (ID) MMAD GSD 4.8 mm  65 nm 1.3  14 mm 516 nm3.3

As can be seen above, as the tube diameter became larger so did theparticle size. Additionally, as the diameter became larger, the GSD alsobecame larger. As the tube becomes larger, it is believed that thevaporized gas is introduced into a smaller segment of the mixing gasbecause the gas is being introduced as a point source leading to unevenmixing, which results in a large GSD.

Example 5 In Vitro Results Using Example 800

To demonstrate effectiveness of example 800, a 4-inch long piece ofaluminum was fitted with a 150-watt cartridge heater at one end. Theheater was powered with a variac AC power transformer. The thickness ofthe aluminum was designed to ensure that heat would transverse from oneend of the aluminum to the other in approximately 30 seconds.

On the topside of the aluminum, an indentation was machined to hold thecompound and to hold one of two top covers. The indentation for thecompound was approximately 3.5 inches long and 0.4 inches wide. Theindentation was 0.025 inches deep, and was filled with 1 mg of DOP.

The first top consisted of a sheet of flat glass placed 0.04 inchesabove the heated surface, creating an airway. At the exit end an outletwas fitted allowing the air to be drawn into an analytical measurementdevice. Air was made to flow through the airway at a rate of 15liters/minute.

In the second configuration, the top was replaced with a half cylindermade of glass. This increased the cross sectional area of the airway byan order of magnitude.

Particle size was measured with both configurations and shown to beaffected by the cross sectional area of the airway.

Results from the thermal gradient test are set forth in Table 5 below:

TABLE 5 Cover size and cross-section MMAD GSD Small  92 nm 1.4 Big 650nm unknown

As shown above, the results confirm that as the cross section becomeslarger, so does the particle size.

Example 6 In Vitro Results Using Example 900

In this example for producing aerosols, airway passage 910 wasconstructed from 18 mm diameter glass tubing. However, the passage canbe made in any shape with a comparable cross-sectional area and out ofany suitable material. The screen size, mesh, and the amount of compoundwere chosen in this example so that a gas could pass through the screenwithout interference once the compound had been deposited on it.

Because the internal resistance of the screen was low, i.e., between0.01 and 0.2 ohms, the discharge rate (the RC time constant) of thecapacitor was rapid, and on the order of a few milliseconds, i.e. lessthan 20 milliseconds, preferably in the range of about 2 to about 10milliseconds. Upon discharge of capacitor 902 and the subsequent heatingof screen 902, the deposited compound was rapidly vaporized. Because airmoved through screen 902, the vaporized compound rapidly mixed with airand cooled.

The compound was deposited onto the fine stainless steel screen, e.g.,200 mesh, made from 316 stainless steel, having measurements of 2.54cm.×2.54 cm. The current from the capacitor was passed between one edgeand another. It was not necessary to heat the screen to temperaturescomparable to the thin foil in Example 1, because the compound vaporizedat a lower temperature due to the rapid air movement. Rapid air movementallowed the compound to vaporize at a lower vapor pressure, sinceairflow constantly removed compound vapors from the surface as soon asthey were formed. Thus, the compound vaporized at a lower temperaturewithout decomposition.

Deposition of the compound onto the screen was accomplished by mixingthe compound with an organic solvent until the compound dissolved. Theresulting solution was then applied to the fine stainless steel screen902 and the solvent was allowed to evaporate. The screen was theninserted into holder 940 that electrically connected two sides of screen902 to the power circuit described above.

A 10,000 mF capacitor was discharged while the gas was passing throughscreen 902. The rapid heat up of the screen resulted in a rapidvaporization of the compound into the gas. Thus the resulting vaporizedcompound was mixed into a small volume of the gas. Because the ratio ofthe mass of the compound to the volume of the mixing gas was large, afine (1-3 micron diameter) particle aerosol was made.

Example 7 General Procedure for Screening Drugs to DetermineAerosolization Preferability

Drug (1 mg) is dissolved or suspended in a minimal amount of solvent(e.g., dichloromethane or methanol). The solution or suspension ispipetted onto the middle portion of a 3 cm by 3 cm piece of aluminumfoil. The coated foil is wrapped around the end of a 1½ cm diameter vialand secured with parafilm. A hot plate is preheated to approximately300° C., and the vial is placed on it foil side down. The vial is lefton the hotplate for 10 s after volatilization or decomposition hasbegun. After removal from the hotplate, the vial is allowed to cool toroom temperature. The foil is removed, and the vial is extracted withdichloromethane followed by saturated aqueous NaHCO₃. The organic andaqueous extracts are shaken together, separated, and the organic extractis dried over Na₂SO₄. An aliquot of the organic solution is removed andinjected into a reverse-phase HPLC with detection by absorption of 225nm light. A drug is preferred for aerosolization where the purity of thedrug isolated by this method is greater than 85%. Such a drug has adecomposition index less than 0.15. The decomposition index is arrivedat by subtracting the percent purity (i.e., 0.85) from 1.

One of ordinary skill in the art can combine the foregoing examples ormake various other examples and aspects of the method and device of thepresent invention to adapt them to specific usages and conditions. Assuch, these changes and modifications are properly, equitably, andintended to be, within the full range of equivalents of the followingclaims.

What is claimed is:
 1. A device for delivering loxapine containingaerosols comprising: a housing comprising an inlet, an outlet; and, anairway extending from the inlet to the outlet; wherein the airwaycomprises a gas/vapor mixing area, wherein the airway includes asubassembly, and wherein the subassembly includes a metallic substrate,and wherein a composition comprising loxapine is coated as a thin filmbetween 10μ and 10 nm in thickness on the substrate.